Mycobacterium tuberculosis, the primary agent of tuberculosis, infects half of the world's population and is one of the most important diseases in the world from the standpoint of human morbidity and mortality. M. tuberculosis has also emerged as a highly prevalent opportunistic pathogen in AIDS patients. A safe and effective vaccine against M. tuberculosis is sorely needed. The development of such a vaccine is the ultimate goal of the studies proposed in this application. This proposal seeks to identify molecular determinants of cell-mediated immunity and protective immunity to M. tuberculosis in humans. Preliminary investigations have demonstrated the existence of immunoprotective molecules of M. tuberculosis and laid the foundation for further studies aimed at identifying molecules that are candidates for a subunit vaccine. Thus, these studies hold great promise for the development of an effective vaccine against tuberculosis in the near future. Specific aims of this proposal are to: a) Identify M. tuberculosis proteins which induce cell-mediated immune responses in guinea pigs with pulmonary tuberculosis; b) determine it immunization of guinea pigs with selected M. tuberculosis proteins induces specific cell-mediated and humoral immune responses; c) determine if immunization of guinea pigs with selected M. tuberculosis proteins that induce cell-mediated immune responses establishes protective immunity to aerosol challenge with virulent M. tuberculosis; d) determine optimal conditions for induction of protective immunity by selected M. tuberculosis proteins; e) determine if immunization of guinea pigs with a combination of immunoprotective proteins induces a higher level of protective immunity than single immunogens; f) determine if M. tuberculosis proteins that induce cell-mediated and protective immunity in guinea pigs are expressed in human monocytes infected with M. tuberculosis; g) determine if humans previously exposed to M. tuberculosis develop a cell-mediated immune response to M. tuberculosis proteins that induce cell-mediated and protective immunity in guinea pigs; h) determine if immunoprotective proteins contain immunodominant regions across human MHC types.